P664: GRADING QUALITY OF EVIDENCE AND STRENGTH OF RECOMMENDATIONS FOR THE TREATMENT OF RELAPSED/REFRACTORY CLL.
Authors: S. Molica, C. Patti, P. Sportoletti, A. Chiarenza, A. M. Giordano, F. Chiurazzi, N. Di Renzo, P. Musto, F. Pane, F. Di Raimondo, L. Trentin, F. R. Mauro, D. Giannarelli
Journal: HemaSphere (2022)

Background: Changes in the treatment landscape of CLL have complicated the decision-making processes, especially in the context of relapsed/refractory (R/R) disease. In this setting current guidelines do not provide clear information on the sequencing of targeted agents (TAs). Aims: With this in mind a series of evidence-based recommendations were produced to support pts, clinicians, and other health care professionals in their decisions about the management of R/R CLL. Methods: A multidisciplinary panel that included specialists in methodology, CLL management, and hematology, performed a systematic review of the literature using the databases MEDLINE, EMBASE, and the Cochrane Library, then participated in a virtual consensus conference held at the end of December 2021. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to formulate recommendations. Specifically, the strength of recommendations was determined by the balance between desirable and undesirable consequences of alternative management strategies, quality of evidence, variability in values, preferences, and resource used. Results: Firstly, the panelists prioritized 10 scientific questions in the context of 4 specific scenarios of R/R CLL: (1) relapse after frontline chemo-immunotherapy (CIT), (2) progression of disease (PD) while receiving ibrutinib (IBR), (3) progression after treatment with venetoclax (VEN), and (4) impact of adherence to IBR or VEN on the clinical outcome. The following recommendations were produced: 1- A TA should be offered to all pts relapsing after first-line CIT (strong recommendation based on high-quality evidence). In absence of head-to-head trials comparing a BTKi vs an anti-BCL2 inhibitor, the panel suggests a patient-oriented choice consisting of either continuous BTKi (i.e., IBR or acalabrutinib) or time-limited (TL) VEN-based therapy in both standard or high genomic risk (conditional recommendation based on moderate-quality evidence). Remarks: TL VEN-based regimen is more cost-effective than continuous IBR. 2- The panel recommends switching to VEN for those pts who experience PD whilst on a BTKi (in absence of a valid alternative the recommendation becomes strong even if the quality evidence is moderate). There is no evidence to recommend the combination of VEN plus rituximab or an alternative covalent BTKi over VEN single agent (conditional recommendation based on low certainty in the evidence of effects). Noncovalent BTKi pirtobrutinib needs validation in phase 3 studies. 3- The panel recommends utilizing a BTKi monotherapy instead of re-challenging VEN for pts who have progressed after completing VEN-based therapy (conditional recommendation based on low certainty in the evidence of effects). 4- Finally, panelists agreed that the impact of adherence to IBR or VEN on PFS in R/R pts is supported by a low quality of evidence (conditional recommendation based on low certainty in the evidence of effects). Summary/Conclusion: These evidence-based consensus recommendations strongly support the use of a TA in R/R CLL patients. The choice between TL and continuous TA is patient-oriented with the remark that a TL approach is cost-effective within current pricing structures. A cross-over approach to an alternative TA is suggested in pts progressing on BTKi or BCL2i. However, these recommendations are guided by the fundamental principle that optimal patient care involves ongoing discussions between clinicians and pts, continuously addressing goals of care and the relative risk-benefit balance of treatment.